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Psychiatric Conditions Attempts to Confirm Signal John McLane, Ph.D. Roche Medical Science and Safety. 9/5/00. Clinical Overview Pharmaco-epidemiological Assessment Clinical Analysis of Spontaneous Reports Additional Assessments Biological plausibility Risk Management.
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Psychiatric ConditionsAttempts to Confirm SignalJohn McLane, Ph.D.Roche Medical Science and Safety 9/5/00
Clinical Overview Pharmaco-epidemiological Assessment Clinical Analysis of Spontaneous Reports Additional Assessments Biological plausibility Risk Management
Assessment Strategy to Confirm Signal • Post-approval analysis • Retrospective analysis • Prospective analysis 9/5/00
Retrospective Epidemiological Analysis Relative Risk - Accutane versus Antibiotic Objective • Relative risk for psychiatric disorders Methods • Population-based epidemiological study • Retrospective matched-control cohort • Analysis of prevalence rates for a variety of psychiatric disorders and suicide/suicide attempts 9/5/00
Retrospective AnalysisEpidemiological Data Source • Two Validated Healthcare Databases • Canadian Saskatchewan Health Database (SASK) • Accutane users (n = 7,195) • antibiotic drug therapy (n = 13,700) • UK General Practice Research Database (GPRD) • Accutane users (n = 340) • antibiotic drug therapy (n = 676) 7/11/00
Relative Risk for Disorders SASK Database • Current Accutane use: RR= 1.0 (95% CI 0.9-1.3) • Recent Accutane use: RR= 0.9 (95% CI 0.6-1.4) • Current antibiotics use: RR= 1.3 (95% CI 1.0-1.5) • Recent antibiotics use: RR= 0.9 (95% CI 0.7-1.1) • Prior psychiatric history emerged as the only predictor for the above outcome 9/5/00
Accutane and Antidepressant Prescriptions:Symmetry Analysis of Prescription Sequence • Accutane did not show effect on prescriptions for antidepressants in symmetry analysis • Prescription Sequence ratio = A/B, where A = # pts. prescribed Accutane before antidepressants B = # pts. prescribed Accutane after antidepressants. • Ratio near unity indicates no effect *Hallas J. Epidemiology 1996; 7:478-484
Accutane and Antidepressant Prescribing*Prescription Sequence Symmetry Analysis Antidepressant Drugs Accutane PrescribedBefore/After (A/B) Adjusted Rate Ratio*(95% CI) All Amine SSRI “Other” 1,382 / 1,439 174 / 200 874 / 861 334 / 378 0.97 (0.92-1.02) 0.90 (0.78-1.04) 0.99 (0.93-1.02) 0.95 (0.85-1.05) Adjusted rate ratio was less than one within each class and for all antidepressants *Synergy Pharmacy Claims Database, June 1999 - March 2000 adjusted for changes in prescribing trends during analysis period
Minocycline and Antidepressant Prescribing* Prescription Sequence Symmetry Analysis Antidepressant Drugs Minocycline Prescribed Before/After (A/B) Adjusted Rate Ratio(95% CI) All Amine SSRI “Other” 3,609 / 3,751 494 / 569 2,277 / 2,170 838 / 1,012 0.98 (0.95-1.02) 1.01 (0.93-1.10) 1.00 (0.96-1.04) 0.94 (0.88-1.00) *Synergy Pharmacy Claims Database, June 1999 - March 2000 adjusted for changes in trends during analysis period
Prospective Analysis of Signal • Evaluate in clinical trial using 2 tools • Mood assessment questionnaire • Beck Depression Inventory (BDI-II) • Evaluate 600 patients treated with one of 2 formulations of isotretinoin • Obtain baseline values and end of treatment values • At monthly visits: Mood assessment questionnaire
Distribution of Change in Grade on BDI-II Treatment Group Accutane NF Accutane Change in Grade N N -2 4 1 -1 7 10 0 283 283 +1 3 5 +2 2 1 BDI-II Grades Minimal 0-13 (– indicates decrease grade / + increase) Mild 14-19 Moderate 20-29 Severe 30-63 (table 10 ISS)
Change in BDI-II ScoresBaseline to Week 20 Accutane NF Accutane N = 263 N =255 BDI Score Baseline Week 20 Baseline Week 20 Mean SD 3.5 4.6 1.7 3.1 3.6 4.5 1.9 3.7 Range 0 - 24 0 - 21 0 - 29 0 - 28 PSY 207, (1492), 9/5/00
Clinical Overview Pharmaco-epidemiological Assessment Clinical Analysis of Spontaneous Reports Additional Assessments Biological Plausibility Risk Management
CNS Relationships With RetinoidsRats and Mice • Specific dopamine enriched brain regions have retinoid receptors (cortex, hippocampus, caudate/putamen, nucleus accumbens, olfactory tubercle) • Localization of proteins differs from localization by mRNA • Dopamine 2 receptor genes have retinoid response elements • Isotretinoin can be found in the brain after injections Zetterstrom et al 1999, Krezel, 1999, Le Doze et al. 2000
Biological Summary • Although some of the component factors are in place, retinoids have not been shown to activate genes to induce behavioral/psychiatric changes • In mice lacking retinoid receptor genes no behavioral effects other than long term memory (Long Term Potentiation/Depression) • Lack of evidence demonstrating functionality of retinoid signaling pathways in the mature CNS
Conclusion • All available evidence does not confirm signal • Biological plausibility is not established • Background disease rate in population warrants attention to signs and symptoms of psychosocial disturbance by Dermatologists
Clinical Overview Pharmaco-epidemiological Assessment Clinical Analysis of Spontaneous Reports Additional Analysis Biological Feasibility Risk Management